α,α-Diaryl-4-aryl-4-hydroxyl-1-piperidinebutanamide, N-oxides and pharmaceutical use

ABSTRACT

Antidiarrheal active α,α-diaryl-4-aryl-4-hydroxy-1-piperidinebutanamide, N-oxides, compositions containing the same and methods of treating diarrhea.

This is a continuation of of application Ser. No. 888,606, filed July23, 1986, now U.S. Pat. No. 4,824,853, which is a continuation-in-partof our copending application Ser. No. 786,566, filed Oct. 11, 1985, nowabandoned.

BACKGROUND OF THE INVENTION

In U.S. Pat. No. 3,714,159, there are described2,2-diaryl-4-(4'-hydroxy-piperidino)-butyramides which compounds aretaught to possess useful antidiarrheal and analgesic activities. Thecompounds of the present invention differ therefrom by the fact thatthey invariably contain a 1-piperidine oxide moiety and by theirimproved pharmacological properties.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

The present invention is concerned with novelα,α-diaryl-4-aryl-4-hydroxy-1-piperidinebutanamide, N-oxides which maystructurally be represented by the formula: ##STR1## thepharmaceutically acceptable acid addition salts and stereochemicallyisomeric forms thereof, wherein

R is hydrogen or methyl;

Ar¹ and Ar² are, each independently, phenyl or halophenyl;

Alk is --CH₂ --CH₂ -- or --CH₂ --CH(CH₃)--;

R¹ and R² are, each independently, hydrogen, C₁₋₆ alkyl, phenylmethyl or2-propenyl or R¹ and R² combined with the nitrogen atom bearing said R¹and R² may form a pyrrolidinyl, piperidinyl, C₁₋₆ alkylpiperidinyl,4-morpholinyl or 2,6-di(C₁₋₆ alkyl)-4-morpholinyl radical;

Ar³ is phenyl being optionally substituted with up to 3 substituentsselected from the group consisting of C₁₋₆ alkyl, C₁₋₆ alkyloxy, haloand trifluoromethyl.

As used in the foregoing definitions the term halo is generic to fluoro,chloro, bromo and iodo: "C₁₋₆ alkyl" is meant to include straight andbranched saturated hydrocarbon radicals, having from 1 to 6 carbonatoms, such as, for example, methyl, ethyl, 1-methylethyl,1,1-dimethylethyl, propyl, butyl, pentyl, hexyl and the like.

Preferred compounds within the invention are those wherein R¹ and R² areboth methyl and Ar¹ and Ar² are both phenyl.

Particularly preferred compounds are those preferred compounds whereinAr³ is phenyl being optionally substituted with one or two substituentsindependently selected from halo and trifluoromethyl.

More particularly preferred compounds within the invention are selectedfrom the group consisting of4-(4-chlorophenyl)-4-hydroxy-N,N-dimethyl-α,α-diphenyl-1-piperidinebutanamide,N-oxide, the pharmaceutically acceptable acid addition salts andstereoisomeric forms thereof.

The most preferred compounds within the invention are selected from thegroup consisting oftrans-4-(4-chlorophenyl)-4-hydroxy-N,N-dimethyl-α,α-diphenyl-1-piperidinebutanamide,N-oxide and the pharmaceutically acceptable acid addition salts thereof.

The compounds of formula (I) may generally be prepared by N-oxidating astarting material of formula ##STR2## said N-oxidation reaction maygenerally be carried out by reacting the starting material of formula(II) with an appropriate organic or inorganic peroxide. Appropriateinorganic peroxides comprise, for example, hydrogen peroxide, alkalimetal or earth alkaline metal peroxides, e.g. sodium peroxide, potassiumperoxide, barium peroxide and the like; appropriate organic peroxidesmay comprise peroxy acids such as, for example, benzenecarboperoxoicacid or halo substituted benzenecarbo-peroxoic acid, e.g.3-chlorobenzenecarboperoxoic acid and the like, peroxoalkanoic acids,e.g. peroxoacetic acid and the like, alkylhydroperoxides, e.g. t.butylhydroperoxide and the like. Suitable solvents are, for example, water,lower alkanols, e.g. methanol, ethanol, propanol, butanol and the like,hydrocarbons, e.g. benzene, methylbenzene, dimethylbenzene and the like,ketones, e.g. 2-propanone, 2-butanone and the like, halogenatedhydrocarbons, e.g. dichloromethane, trichloromethane and the like, andmixtures of such solvents. In order to enhance the reaction rate, it maybe appropriate to heat the reaction mixture.

In all of the foregoing and in the following preparations, the reactionproducts may be isolated from the reaction mixture and, if necessary,further purified according to methodologies generally known in the art.

The compounds of formula (I) have basic properties and, consequently,they may be converted to their therapeutically active non-toxic acidaddition salt forms by treatment with appropriate acids, such as, forexample, inorganic acids, such as hydrohalic acid, e.g. hydrochloric,hydrobromic and the like, and sulfuric acid, nitric acid, phosphoricacid and the like; or organic acids, such as, for example, acetic,propanoic, hydroxyacetic, 2-hydroxy-propanoic, 2-oxopropanoic,ethanedioic, propanedioic, butanedioic, (Z)-2-butenedioic,(E)-2-butenedioic, 2-hydroxybutanedioic, 2,3-dihydroxybutanedioic,2-hydroxy-1,2,3-propanetricarboxylic, methanesulfonic, ethanesulfonic,benzenesulfonic, 4-methylbenzenesulfonic, cyclohexanesulfamic, benzoic,2-hydroxybenzoic, 3-phenyl-2-propenoic, α-hydroxybenzeneacetic,4-amino-2-hydroxybenzoic and the like acids. Conversely the salt formcan be converted by treatment with alkali into the free base form.

The intermediates of formula (II) are known compounds and can beprepared according to the procedures described in U.S. Pat. No.3,714,159.

From formula (I) it is evident that the compounds of this invention mayhave several asymmetric carbon atoms in their structure. Each of thesechiral centers may be present in a R- and a S-configuration, this R- andS-notation being in correspondence with the rules described in J. Org.Chem., 35, 2849-2867 (1970).

Pure stereochemically isomeric forms of the compounds of formula (I) maybe obtained by the application of art-known procedures. Diastereoisomersmay be separated by physical separation methods such as selectivecrystallization and chromatographic techniques, e.g., counter currentdistribution, and enantiomers may be separated from each other by theselective crystallization of their diastereomeric salts with opticallyactive acids.

Pure stereochemically isomeric forms may also be derived from thecorresponding pure stereochemically isomeric forms of the appropriatestarting materials, provided that the reaction occursstereospecifically.

It is evident that the cis and trans diastereomeric racemates may befurther resolved into their optical isomers, cis(+), cis(-), trans(+)and trans(-) by the application of methodologies known to those skilledin the art.

Stereochemically isomeric forms of the compounds of formula (I) arenaturally intended to be embraced within the scope of the invention.

In some compounds and starting materials the stereochemicalconfiguration is not experimentally determined. In those cases it isconventionally agreed to designate the stereochemically isomeric formwhich is first isolated as "A" and the second as "B", without furtherreference to the actual stereochemical configuration.

The compounds of formula (I), their pharmaceutically acceptableacid-addition salts and stereoisomeric forms possess usefulpharmacological properties. They show antidiarrheal activity, whichactivity is evidenced by the experimental data obtained in, for example,the "Castor Oil Test in Rats".

The compounds of formula (I), their pharmaceutically acceptableacid-addition salts and stereoisomeric forms are particularly attractivedue to the strongly decreased central effects as compared with theprior-art compounds of U.S. Pat. No. 3,714,159. This can be demonstratedby the results of, for example, the "Tail Withdrawal Test in Rats" whichcan be considered as an indicator for the occurrence of central effects.The compounds of the present invention are also attractive due to theirfavourable toxicity, particularly when compared to the toxicity of theprior-art compounds of U.S. Pat. No. 3,714,159.

Due to their useful pharmacological properties the compounds of formula(I), their pharmaceutically acceptable acid addition salts andstereoisomeric forms can be used in the treatment of diarrhea.

Due to the absence of undesired central effects, they are particularlyuseful in the treatment of diarrhea in subjects where medicines havingsaid undesired central effects can be harmful, for example, in thetreatment of children and infants.

In view of their useful antidiarrheal properties, the subject compoundsmay be formulated into various pharmaceutical forms for administrationpurposes.

To prepare the pharmaceutical compositions of this invention, aneffective amount of the particular compound, in base or acid-additionsalt form, as the active ingredient is combined in intimate admixturewith a pharmaceutically acceptable carrier, which carrier may take awide variety of forms depending on the form of preparation desired foradministration. These pharmaceutical compositions are desirably inunitary dosage form suitable, preferably, for administration orally,rectally or by parenteral injection. For example, in preparing thecompositions in oral dosage form, any of the usual pharmaceutical mediamay be employed, such as, for example, water, glycols, oils, alcoholsand the like in the case of oral liquid preparations such assuspensions, syrups, elixirs and solutions; or solid carriers such asstarches, sugars, kaolin, lubricants, binders, disintegrating agents andthe like in the case of powders, pills, capsules and tablets. Because oftheir ease in administration, tablets and capsules represent the mostadvantageous oral dosage unit form, in which case solid pharmaceuticalcarriers are obviously employed. For parenteral compositions, thecarrier will usually comprise sterile water, at least in large part,though other ingredients, for example, to aid solubility, may beincluded. Injectable solutions, for example, may be prepared in whichthe carrier comprises saline solution, glucose solution or a mixture ofsaline and glucose solution. Injectable suspensions may also be preparedin which case appropriate liquid carriers, suspending agents and thelike may be employed. Acid addition salt of (I) due to their increasedwater solubility over the corresponding base form, are obviously moresuitable in the preparation of aqueous compositions.

It is especially advantageous to formulate the aforementionedpharmaceutical compositions in dosage unit form for ease ofadministration and uniformity of dosage. Dosage unit form as used in thespecification and claims herein refers to physically discrete unitssuitable as unitary dosages, each unit containing a predeterminedquantity of active ingredient calculated to produce the desiredtherapeutic effect in association with the required pharmaceuticalcarrier. Examples of such dosage unit forms are tablets (includingscored or coated tablets), capsules, pills, powder packets, wafers,injectable solutions or suspensions, teaspoonfuls, tablespoonfuls andthe like, and segregated multiples thereof.

In view of the usefulness of the subject compounds in the treatment ofdiarrhea, it is evident that the present invention provides a method oftreating warm-blooded animals suffering from diarrhea, said methodcomprising the systemic administration of a pharmaceutically effectiveamount of a compound of formula (I), a pharmaceutically acceptableacid-addition salt or stereoisomeric form thereof.

Those of skill in treating warm-blooded animals suffering from diarrheacould easily determine the effective amount from the test resultspresented here. In general it is contemplated that an effective amountwould be from 0.001 mg/kg to 20 mg/kg body weight, preferably from 0.005mg/kg to 5 mg/kg body weight and more preferably from 0.01 to 0.1 mg/kgbody weight.

The following examples are intended to illustrate and not to limit thescope of the present invention. Unless otherwise stated all partstherein are by weight.

EXAMPLES (A) Preparation of Final Compounds Example 1

A mixture of 26.5 parts of4-(4-chlorophenyl)-4-hydroxy-N,N-dimethyl-α,α-diphenyl-1-piperidinebutanamide,17.1 parts of a hydrogen peroxide solution 30%, 200 parts of methanoland 315 parts of methylbenzene was stirred first for 20 hours at 60° C.and then for 96 hours at 70° C. The reaction mixture was evaporated. Theresidue was purified by column-chromatography (HPLC) over silica gelusing a mixture of trichloromethane, methanol and methanol, saturatedwith ammonia, (90:9:1 by volume) as eluent. The pure fractions werecollected and the eluent was evaporated. The residue was crystallizedfrom a mixture of 2,2'-oxybispropane and a small amount of methanol. Theproduct was filtered off and dried in a dry-pistol with methylbenzenefor 30 minutes at reflux temperature, yielding 2.0 parts (7%) oftrans-4-(4-chlorophenyl)-4-hydroxy-N,N-dimethyl-α,α-diphenyl-1-piperidinebutanamide.N-oxide; mp. 149.7° C. (1).

Example 2

A mixture of 21.5 parts of4-[4-chloro-3-(trifluoromethyl)phenyl]-4-hydroxy-N,N-dimethyl-α,.alpha.-diphenyl-1-piperidinebutanamide,8.6 parts of a hydrogen peroxide solution 30% and 260 parts of4-methyl-2-pentanone was stirred for 24 hours at 80° C. After cooling inan ice-bath, the precipitated product was filtered off and dried,yielding 10.4 parts (46%) of(A)-4-[4-chloro-3-(trifluoromethyl)phenyl]-4-hydroxy-N,N-dimethyl-α,α-diphenyl-1-piperidinebutanamide,N-oxide; mp. 185.3° C. (2).

Example 3

A mixture of 20 parts of4-[4-chloro-3-(trifluoromethyl)phenyl]-4-hydroxy-N,N-dimethyl-α,.alpha.-diphenyl-1-piperidinebutanamide,8 parts of a hydrogen peroxide solution 30% and 240 parts of4-methyl-2-pentanone was stirred for 24 hours at 80° C. The reactionmixture was cooled in an ice bath. The precipitated product was filteredoff and the filtrate was evaporated. The residue was purified by columnchromatography over silica gel using a mixture of trichloromethane andmethanol (90:10 by volume) as eluent. The second fraction was collectedand the eluent was evaporated. The residue was further purified bycolumn chromatography (HPLC) over silica gel using a mixture of hexane,trichloromethane, methanol and ammonium hydroxide (45:50:5:0.05 byvolume) as eluent. The pure fractions were collected and the eluent wasevaporated. The residue was stirred in 2,2'-oxybispropane. The productwas filtered off and dried, yielding 1.2 parts of(B)-4-[4-chloro-3-(trifluoromethyl)phenyl]-4-hydroxy-N,N-dimethyl-α,α-diphenyl-1-piperidinebutanamide,N-oxide sesquihydrate; mp. 152.9° C. (3).

Example 4

To a stirred solution of 133.0 parts of4-(4-chlorophenyl)-4-hydroxy-N,N-dimethyl-α,α-diphenyl-1-piperidinebutanamidein 2000 parts of 4-methyl-2-pentanone were added 57.0 parts of ahydrogen peroxide solution 30%. The whole was stirred for 20 hours at80° C. After cooling overnight, the precipitate was filtered off(filtrate I was set aside) and boiled in 4-methyl-2-pentanone. Theundissolved part was filtered off and the filtrate, together withfiltrate I, was evaporated. The residue was purified by columnchromatography over silica gel using a mixture of trichloromethane andmethanol (90:10 by volume) as eluent. The second fraction was collectedand the eluent was evaporated. The residue was purified twice: first bycolumn chromatography over silica gel using a mixture oftrichloromethane, methanol and ammonium hydroxide (90:9:1 by volume) aseluent and then by column chromatography (HPLC) over silica gel using amixture of trichloromethane, hexane, methanol and methanol, saturatedwith ammonia, (45:45:9:1 by volume) as eluent. The pure fractions werecollected and the eluent was evaporated. The residue was stirred in2,2'-oxybispropane. The product was filtered off and dried, yielding 2.3parts ofcis-4-(4-chlorophenyl)-4-hydroxy-N,N-dimethyl-α,α-diphenyl-1-piperidinebutanamide,N-oxide; mp. 146.6° C. (4).

In a similar manner there are also prepared: ##STR3##

    __________________________________________________________________________    No.                                                                              Ar.sup.1                                                                           Ar.sup.2                                                                           R  R.sup.1                                                                              R.sup.2   R.sup.3                                                                            R.sup.4                                                                            R.sup.5                                                                           Alk                            __________________________________________________________________________    5  C.sub.6 H.sub.5                                                                    C.sub.6 H.sub.5                                                                    H  (CH.sub.2).sub.4 3-Cl H    H   (CH.sub.2).sub.2               6  C.sub.6 H.sub.5                                                                    C.sub.6 H.sub.5                                                                    H  (CH.sub.2).sub.2O(CH.sub.2).sub.2                                                              3-Cl H    H   (CH.sub.2).sub.2               7  C.sub.6 H.sub.5                                                                    C.sub.6 H.sub.5                                                                    H  (CH.sub.2).sub.5 2-CF.sub.3                                                                         3-Cl H   (CH.sub.2).sub.2               8  C.sub.6 H.sub.5                                                                    C.sub.6 H.sub.5                                                                    H  C.sub.2 H.sub.5                                                                      C.sub.2 H.sub.5                                                                         2-CF.sub.3                                                                         3-Cl H   (CH.sub.2).sub.2               9  C.sub.6 H.sub.5                                                                    C.sub.6 H.sub.5                                                                    H  (CH.sub.2).sub.2O(CH.sub.2).sub.2                                                              3-CH.sub.3                                                                         H    H   (CH.sub.2).sub.2               10 C.sub.6 H.sub.5                                                                    C.sub.6 H.sub.5                                                                    H  C.sub.2 H.sub.5                                                                       C.sub.2 H.sub.5                                                                        3-F  H    H   (CH.sub.2).sub.2               11 C.sub.6 H.sub.5                                                                    C.sub.6 H.sub.5                                                                    H  CH.sub.3                                                                             CH.sub.3  H    H    H   CH.sub.2CH(CH.sub.3)           12 C.sub.6 H.sub.5                                                                    C.sub.6 H.sub.5                                                                    H  CH.sub.3                                                                             CH.sub.3  3-Br H    H   (CH.sub.2).sub.2               13 C.sub.6 H.sub.5                                                                    C.sub.6 H.sub.5                                                                    H  (CH.sub.2).sub.4 2-Cl 3-Cl H   (CH.sub.2).sub.2               14 C.sub.6 H.sub.5                                                                    C.sub.6 H.sub.5                                                                    H  C.sub.3 H.sub.7                                                                      C.sub.3 H.sub.7                                                                         3-Cl H    H   (CH.sub.2).sub.2               15 C.sub.6 H.sub.5                                                                    C.sub.6 H.sub.5                                                                    H  C.sub.4 H.sub.11                                                                     C.sub.4 H.sub.11                                                                        3-Cl H    H   (CH.sub.2).sub.2               16 C.sub.6 H.sub.5                                                                    C.sub.6 H.sub.5                                                                    H                                                                                                 3-Cl H    H   (CH.sub.2).sub.2               17 C.sub.6 H.sub.5                                                                    C.sub.6 H.sub.5                                                                    H  CH.sub.3                                                                             CH.sub.3  1-CH.sub.3                                                                         1-CH.sub.3                                                                         H   (CH.sub.2).sub.2               18 C.sub.6 H.sub.5                                                                    C.sub.6 H.sub.5                                                                    H                                                                                 ##STR4##        3-Cl H    H   (CH.sub.2).sub.2               19 C.sub.6 H.sub.5                                                                    C.sub.6 H.sub.5                                                                    H  C.sub.2 H.sub.5                                                                      CH.sub.3  3-Cl H    H   (CH.sub.2).sub.2               20 C.sub.6 H.sub.5                                                                    C.sub.6 H.sub.5                                                                    H                                                                                 ##STR5##        3-Cl H    H   (CH.sub.2).sub.2               21 C.sub.6 H.sub.5                                                                    C.sub.6 H.sub.5                                                                    H  CH.sub.3                                                                             CH.sub.2C.sub.6 H.sub.5                                                                 3-Cl H    H   (CH.sub.2 ).sub.2              22 C.sub.6 H.sub.5                                                                    C.sub.6 H.sub.5                                                                    CH.sub.3                                                                         CH.sub.3                                                                             CH.sub.3  2-CF.sub.3                                                                         3-Cl H   (CH.sub.2).sub.2               23 C.sub.6 H.sub.5                                                                    C.sub.6 H.sub.5                                                                    H  CH.sub.3                                                                             CH.sub.3  2-CH.sub.3                                                                         3-CH.sub.3                                                                         4-CH.sub.3                                                                        (CH.sub.2).sub.2               24 C.sub.6 H.sub.5                                                                    C.sub.6 H.sub.5                                                                    H  CH.sub.2CHCH.sub.2 /CH.sub.2CHCH.sub.2                                                         3-Cl H    H   (CH.sub.2).sub.2               25 C.sub.6 H.sub.5                                                                    C.sub.6 H.sub.5                                                                    H  CH.sub.3                                                                             C.sub.3 H.sub.7                                                                         3-Cl H    H   (CH.sub.2).sub.2               26 C.sub.6 H.sub.5                                                                    C.sub.6 H.sub.5                                                                    CH.sub.3                                                                         CH.sub.3                                                                             CH.sub.3  2-CF.sub.3                                                                         H    H   (CH.sub.2).sub.2               27 C.sub.6 H.sub.5                                                                    C.sub.6 H.sub.5                                                                    H  CH.sub.3                                                                             i-C.sub.3 H.sub.7                                                                       3-Cl H    H   (CH.sub.2).sub.2               28 C.sub.6 H.sub.5                                                                    C.sub.6 H.sub.5                                                                    H  CH.sub.3                                                                             CH.sub.3  1-OCH.sub.3                                                                        4-OCH.sub.3                                                                        H   (CH.sub.2).sub.2               29 3FC.sub.6 H.sub.4                                                                  3FC.sub.6 H.sub.5                                                                  H  CH.sub.3                                                                             CH.sub. 3 3-Cl H    H   (CH.sub.2).sub.2               30 3FC.sub.6 H.sub.4                                                                  C.sub.6 H.sub.5                                                                    H  CH.sub.3                                                                             CH.sub.3  3-Cl H    H   (CH.sub.2).sub.2               31 3FC.sub.6 H.sub.4                                                                  3ClC.sub.6 H.sub.4                                                                 H  CH.sub.3                                                                             CH.sub.3  3-Cl H    H   (CH.sub.2).sub.2               32 C.sub.6 H.sub.5                                                                    C.sub.6 H.sub.5                                                                    H  H      CH.sub.3  3-Cl H    H   (CH.sub.2).sub.2               33 C.sub.6 H.sub.5                                                                    C.sub.6 H.sub.5                                                                    H  H      H         3-Cl H    H   (CH.sub.2).sub.2               34 C.sub.6 H.sub.5                                                                    C.sub.6 H.sub.5                                                                    H  CH.sub.3                                                                             CH.sub.3  2-CF.sub.3                                                                         3-Cl H   CH(CH.sub.3)CH.sub.2           __________________________________________________________________________

(B) Pharmacological Examples Example 5 Castor Oil Test in Rats

Female Wistar rats were fasted overnight. Each animal was treatedintravenously with the desired dose of the compound to be tested. Onehour thereafter, the animal received 1 ml of castor oil orally. Eachanimal was kept in an individual cage and 2 hours after the castor oiltreatment, the presence or absence of diarrhea was noted. The ED₅₀ valuewas determined as that dose in mg/kg body weight, at which no diarrheawas present in 50% of the tested animals. Said ED₅₀ -value for acompound of the present invention and for4-(4-chlorophenyl)-4-hydroxy-N,N-dimethyl-α,α-diphenyl-1-piperidinebutanamide,which compound is generically designated as loperamide and which isdescribed in U.S. Pat. No. 3,714,159, can be found in table I.

Example 6 Tail Withdrawal Test in Rats

Female Wistar rats were fasted overnight. Each animal was treatedintravenously with the desired dose of the compound to be tested. Thethus treated rats were put into individual restraining cages. After theadministration of the test compound, the lower 5 cm portion of the tailwas immersed into a cup filled with water at a constant temperature of55° C. The typical tail withdrawal response was evaluated during a 10seconds period after the immersion. ED₅₀ values in mg/kg body weightwere determined as that dose of the test compound capable of suppressingin 50% of the tested animals the typical tail withdrawal response duringa time period exceeding 10 seconds. Said ED₅₀ values obtained for acompound of the present invention and for4-(4-chlorophenyl)-4-hydroxy-N,N-dimethyl-α,α-diphenyl-1-piperidinebutanamide(i.e. loperamide) are also gathered in table I. From these ED₅₀ -values,it can be concluded that the prior art compound antagonizes the typicaltail withdrawal reflex, while the compound 1 does not show suchactivity.

Example 7 Determination of toxicity

Female Wistar rats were treated with the compound to be tested atvarious dose levels. LD₅₀ values were determined as that dose in mg/kgbody weight being lethal in 50% of the tested animals. Said LD₅₀ valuesobtained for a compound of the present invention and for4-(4-chlorophenyl)-4-hydroxy-N,N-dimethyl-α,α-diphenyl-1-piperidinebutanamide(i.e. loperamide) are also listed in table I. From these values it canbe concluded that the compounds of the present invention show adecreased toxicity.

Example 8 Determination of the safety margin and antidiarrhealspecificity

The safety margin for the antidiarrheal action was determined as theratio of the LD₅₀ value to the ED₅₀ value obtained in the Castor OilTest. The antidiarrheal specificity was determined as the ratio of theED₅₀ value obtained in the Tail Withdrawal Test to the ED₅₀ valueobtained in the Castor Oil Test. These values are also listed in tableI. Both the safety margin for the antidiarrheal action and theantidiarrheal specificity of the compounds of the present invention aresuperior to the same of the prior-art compound.

                  TABLE I                                                         ______________________________________                                              Castor   Tail                                                           Com-  Oil      Withdrawal     Safety   Anti-                                  pound ED.sub.50                                                                              ED.sub.50      Margin   diarrheal                              no.   in mg/kg in mg/kg  LD.sub.50                                                                          antidiarrheal                                                                          specificity                            ______________________________________                                        *     0.095    2.83      5.92 62.3     29.8                                   1     0.21     >20.0     28.3 135      >95                                    ______________________________________                                         *loperamide                                                              

(C) COMPOSITION EXAMPLES

The following formulations exemplify typical pharmaceutical compositionsin dosage unit form suitable for systemic administration to animal andhuman subjects in accordance with the instant invention.

"Active ingredient" (A.I.) as used throughout these examples relates toa compound of formula (I) or pharmaceutically acceptable acid additionsalt thereof.

Example 9: ORAL DROPS

500 Grams of the A.I. was dissolved in 0.5 liters of 2-hydroxypropanoicacid and 1.5 liters of the polyethylene glycol at 60°-80° C. Aftercooling to 30°-40° C. there was added 35 liters of polyethylene glycoland the mixture was stirred well. Then there was added a solution of1750 grams of sodium saccharin in 2.5 liters of purified water and whilestirring there were added 2.5 liters of cocoa flavor and polyethyleneglycol q.s. to a volume of 50 liters, providing an oral drop solutioncomprising 10 milligrams of the A.I. per milliliter. The resultingsolution was filled into suitable containers.

Example 10: ORAL SOLUTION

9 Grams of methyl 4-hydroxybenzoate and 1 gram of propyl4-hydroxybenzoate was dissolved in 4 liters of boiling purified water.In 3 liters of this solution were dissolved first 10 grams of2,3-dihydroxybutanedioic acid and thereafter 20 grams of the A.I. Thelatter solution was combined with the remaining part of the formersolution and 12 liters 1,2,3-propanetriol and 3 liters of sorbitol 70%solution were added thereto. 40 Grams of sodium saccharin were dissolvedin 0.5 liters of water and 2 milliliters of raspberry and 2 millilitersof gooseberry essence were added. The latter solution was combined withthe former, water was added q.s. to a volume of 20 liters providing anoral solution comprising 20 milligrams of the active ingredient perteaspoonful (5 milliliters). The resulting solution was filled insuitable containers.

Example 11: CAPSULES

20 Grams of the A.I., 6 grams sodium lauryl sulfate, 56 grams starch, 56grams lactose, 0.8 grams colloidal silicon dioxide, and 1.2 gramsmagnesium stearate were vigorously stirred together. The resultingmixture was subsequently filled into 1000 suitable hardened gelatingcapsules, comprising each 20 milligrams of the active ingredient.

Example 12: FILM-COATED TABLETS Preparation of tablet core

A mixture of 100 grams of the A.I., 570 grams lactose and 200 gramsstarch was mixed well and thereafter humidified with a solution of 5grams sodium dodecyl sulfate and 10 grams polyvinylpyrrolidone(Kollidon-K 90®) in about 200 milliliters of water. The wet powdermixture was sieved, dried and sieved again. Then there was added 100grams microcrystalline cellulose (Avicel®) and 15 grams hydrogenatedvegetable oil (Sterotex®). The whole was mixed well and compressed intotablets, giving 10.000 tablets, each containing 10 milligrams of theactive ingredient.

Coating

To a solution of 10 grams methyl cellulose (Methocel 60 HG®) in 75milliliters of denaturated ethanol there was added a solution of 5 gramsof ethyl cellulose (Ethocel 22 cps®) in 150 milliliters ofdichloromethane. Then there were added 75 milliliters of dichloromethaneand 2.5 milliliters 1,2,3-propanetriol. 10 Grams of polyethylene glycolwas molten and dissolved in 75 milliliters of dichloromethane. Thelatter solution was added to the former and then there were added 2.5grams of magnesium octadecanoate, 5 grams of polyvinylpyrrolidone and 30milliliters of concentrated colour suspension (Opaspray K-1-2109®) andthe whole was homogenated. The tablet cores were coated with the thusobtained mixture in a coating apparatus.

Example 13: INJECTABLE SOLUTION

1.8 Grams methyl 4-hydroxybenzoate and 0.2 grams propyl4-hydroxybenzoate were dissolved in about 0.5 liters of boiling waterfor injection. After cooling to about 50° C. there were added whilestirring 4 grams lactic acid, 0.05 grams propylene glycol and 4 grams ofthe A.I.

The solution was cooled to room temperature and supplemented with waterfor injection q.s. ad 1 liter volume, giving a solution of 4 milligramsA.I. per milliliters. The solution was sterilized by filtration (U.S.P.XVII p. 811) and filled in sterile containers.

Example 14: SUPPOSITORIES

3 Grams A.I. was dissolved in a solution of 3 grams2,3-dihydroxybutanedioic acid in 25 milliliters polyethylene glycol 400.12 Grams surfactant (SPAN®) and triglycerides (Witepsol 555®) q.s. ad300 grams were molten together. The latter mixture was mixed well withthe former solution. The thus obtained mixture was poured into moulds ata temperature of 37°-38° C. to form 100 suppositories each containing 30milligrams of the active ingredient.

What is claimed is:
 1. The compound4-[4-chloro-3-(trifluoromethyl)phenyl]-4-hydroxy-N,N-dimethyl-α,.alpha.-diphenyl-1-piperidinebutaneamide,N-oxide.
 2. A composition comprising suitable pharmaceutical carriersand as active ingredient an anti-diarrheal effective amount of thecompound4-[4-chloro-3-(trifluoromethyl)phenyl]-4-hydroxy-N,N-dimethyl-α,.alpha.-diphenyl-1-piperidinebutaneamide,N-oxide.
 3. A method of treating warm-blooded animals suffering fromdiarrhea, which method comprises the systemic administration towarm-blooded animals of an effective anti-diarrheal amount of thecompound4-[4-chloro-3-(trifluoromethyl)phenyl]-4-hydroxy-N,N-dimethyl-α,.alpha.-diphenyl-1-piperidine-butaneamide,N-oxide.